Targeting eIF4F Translation Initiation Complex with SBI-756 Sensitizes B Lymphoma Cells to Venetoclax
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE159906 | GEO | 2020/10/25
REPOSITORIES: GEO
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Project description:Targeting eIF4F Translation Initiation Complex with SBI-756 Sensitizes B Lymphoma Cells to Venetoclax
| PRJNA670855 | ENA
Project description:BackgroundThe BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates in indolent blood cancers such as chronic lymphocytic leukaemia. There is a lower response rate to venetoclax monotherapy in diffuse large B-cell lymphoma (DLBCL).MethodsWe tested inhibitors of cap-dependent mRNA translation for the ability to sensitise DLBCL and mantle cell lymphoma (MCL) cells to apoptosis by venetoclax. We compared the mTOR kinase inhibitor (TOR-KI) MLN0128 with SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffolding protein in the eIF4F complex.ResultsTreatment of DLBCL and MCL cells with SBI-756 synergised with venetoclax to induce apoptosis in vitro, and enhanced venetoclax efficacy in vivo. SBI-756 prevented eIF4E-eIF4G1 association and cap-dependent translation without affecting mTOR substrate phosphorylation. In TOR-KI-resistant DLBCL cells lacking eIF4E binding protein-1, SBI-756 still sensitised to venetoclax. SBI-756 selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, leading to a reduction in protein synthesis rates in sensitive cells. When normal lymphocytes were treated with SBI-756, only B cells had reduced viability, and this correlated with reduced protein synthesis.ConclusionsOur data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models.
| S-EPMC7960756 | biostudies-literature
Project description:In eukaryotic cells, protein synthesis typically begins with the binding of eIF4F to the 7-methylguanylate (m7G)cap found on the 5’ end of the majority of mRNAs. Surprisingly, overall translational output remains robust under eIF4F inhibition. The sustained protein synthesis has been largely attributed to cap-independent translation mediated by internal ribosome entry sites (IRES). However, the IRES-driven translation is substrate-specific and largely incompatible with the broad spectrum of eIF4F-resistant translatomes.Here, we report that N6-methyladenosine (m6A)-mediated translation prevails on capped mRNAs and is resistant to eIF4F inactivation.Depletion of the methyltransferase METTL3 selectively inhibits translation of mRNAs bearing 5’UTR methylation, but not mRNAs with 5’ terminal oligopyrimidine (TOP) elements. Mechanistically, we identify ABCF1 as a critical mediator of m6A-promoted translation under both stress and physiological conditions. Supporting the role of ABCF1 in m6A-mediated cap-independent translation, ABCF1-sensitive transcripts largely overlap with METTL3-responsible mRNA targets. By illustrating the scope and the mechanism of translation initiation that is neither cap- nor IRES-dependent, these findingsreshape our current perceptions of cellular translational pathways
2017-07-26 | GSE101865 | GEO
Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.
2019-05-03 | GSE125403 | GEO
Project description:RNA-sequencing was performed to evaluate gene expression changes between ABT-199 (venetoclax) sensitive and resistant matched diffuse large B cell lymphoma cell lines
2024-06-20 | GSE252306 | GEO
Project description:Acute myeloid leukemia (AML) is a hematopoietic cancer characterized by the proliferation and accumulation of aberrant immature myeloid progenitor blasts in bone marrow and peripheral blood. Venetoclax (VEN), a selective B-cell lymphoma 2 (BCL-2) inhibitor, has received FDA approval for AML treatment in combination with hypomethylating agents (HMA). However, treatment failure and therapy resistance present an urgent need for new therapies to overcome VEN resistance and enhance VEN efficacy. We propose inhibition of SUMOylation as a novel therapy with the potential to address this need. SUMOylation regulates protein function by covalently attaching Small Ubiquitin-like MOdifier (SUMO) proteins to target proteins via an enzymatic cascade. Our study aims to evaluate the effects of SUMOylation inhibition on anti-AML activity of VEN and dissert the underlying mechanism.
2024-05-27 | GSE267885 | GEO
Project description:Identification of eukaryotic mRNAs that are translated at reduced cap binding complex eIF4F concentrations using a cDNA microarray. Although most eukaryotic mRNAs need a functional cap binding complex eIF4F for efficient 5' end-dependent scanning to initiate translation, picornaviral, hepatitis C viral, and a few cellular RNAs have been shown to be translated by internal ribosome entry, a mechanism that can operate in the presence of low levels of functional eIF4F. To identify cellular mRNAs that can be translated when eIF4F is depleted or in low abundance and that, therefore, may contain internal ribosome entry sites, mRNAs that remained associated with polysomes were isolated from human cells after infection with poliovirus and were identified by using a cDNA microarray. Approximately 200 of the 7000 mRNAs analyzed remained associated with polysomes under these conditions. Among the gene products encoded by these polysome-associated mRNAs were immediate-early transcription factors, kinases, and phosphatases of the mitogen-activated protein kinase pathways and several protooncogenes, including c-myc and Pim-1. In addition, the mRNA encoding Cyr61, a secreted factor that can promote angiogenesis and tumor growth, was selectively mobilized into polysomes when eIF4F concentrations were reduced, although its overall abundance changed only slightly. Subsequent tests confirmed the presence of internal ribosome entry sites in the 5' noncoding regions of both Cyr61 and Pim-1 mRNAs. Overall, this study suggests that diverse mRNAs whose gene products have been implicated in a variety of stress responses, including inflammation, angiogenesis, and the response to serum, can use translational initiation mechanisms that require little or no intact cap binding protein complex eIF4F. This study is described more fully in Johannes G et al.(1999) Proc Natl Acad Sci U S A 96:13118-23.
2002-06-27 | E-GEOD-62 | biostudies-arrayexpress
Project description:We established acquired venetoclax resistant OCI-LY1R cell line by treating venetoclax sensitive parental OCI-Ly1 cell line with increasing doses of venetoclax up till 1µM. Parental OCI-Ly1 and venetoiclax-resistant OCI-Ly1R cells were treated with vehicle control or decitabine at 1uM for 3 days. We found that decitabine differantially regulated gene expression in venetoclax sensitive and resistant cells. With gene set enrichment analysis, we identified two pathways that were deregulated by decitabine in both cell lines.
2023-07-25 | GSE223598 | GEO
Project description:CRISPR technologies have advanced cancer modelling in mice, but CRISPR activation (CRISPRa) methods have not been exploited in this context. We establish a CRISPRa mouse (dCas9a-SAMKI/+ 38 ) for inducing gene expression in vivo and in vitro. Using dCas9a-SAMKI 39 primary lymphocytes, we induced B cell restricted genes in T cells and vice versa, demonstrating the power of this system. There are limited models of aggressive double hit lymphoma. Therefore, we transactivated pro-survival BCL-2 in Eµ-MycT/+;dCas9a-SAMKI/+ 42 haematopoietic stem and progenitor cells. Mice transplanted with these cells rapidly developed lymphomas expressing high BCL-2 and MYC. Unlike standard Eµ-Myc lymphomas, BCL-2 expressing lymphomas were highly sensitive to the BCL-2 inhibitor venetoclax. We performed genome-wide activation screens in these lymphoma cells and found a dominant role for the BCL-2 protein A1 in venetoclax resistance. Here we show the power of our CRISPRa model for mimicking disease and providing insights into resistance mechanisms towards targeted therapies.
2022-07-08 | GSE205509 | GEO
Project description:Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients.
| S-EPMC4496233 | biostudies-literature